P2‐230: Challenges Associated With Biomarker‐based Classifications Systems for Alzheimer's Disease

Illán‐Gala, Ignacio; Pegueroles, Jordi Malé i; Montal, Víctor; Vilaplana, Eduard; Carmona‐Iragui, María; Alcolea, Daniel; Castilla, Joaquı́n; Leon, Mony J. de; Blesa, Rafael; Lleó, Alberto; Fortea, Juan; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1016/j.jalz.2018.06.917

Cited by 6 publications

(14 citation statements)

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“…For the A and T biomarker group, this assumption holds fairly well, with moderate to high agreement and relatively high correlation coefficients between markers within A and T, respectively. [5][6][7] N biomarkers, however, are poorly correlated and show inadequate agreement. 6,[8][9][10][11] Furthermore, the fact that N biomarkers are suggested to provide staging information implies that individuals with a higher degree of neurodegeneration are assumed to deteriorate more quickly.…”

Section: Classification Of Evidencementioning

confidence: 99%

“…[5][6][7] N biomarkers, however, are poorly correlated and show inadequate agreement. 6,[8][9][10][11] Furthermore, the fact that N biomarkers are suggested to provide staging information implies that individuals with a higher degree of neurodegeneration are assumed to deteriorate more quickly. However, there are few studies that directly compared different N biomarkers in their association with clinical progression or cognitive decline over time.…”

Section: Classification Of Evidencementioning

confidence: 99%

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Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline

et al. 2022

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Background and ObjectivesMultiple biomarkers have been suggested to measure neurodegeneration (N) in the AT(N) framework, leading to inconsistencies between studies. We investigated the association of 5 N biomarkers with clinical progression and cognitive decline in individuals with subjective cognitive decline (SCD).MethodsWe included individuals with SCD from the Amsterdam Dementia Cohort and SCIENCe project, a longitudinal cohort study (follow-up 4±3 years). We used the following N biomarkers: CSF total (t)-tau, medial temporal atrophy visual rating on MRI, hippocampal volume (HV), serum neurofilament light (NfL) and serum glial fibrillary acidic protein (GFAP). We determined correlations between biomarkers. We assessed associations between N biomarkers and clinical progression to mild cognitive impairment or dementia (Cox regression), and MMSE over time (linear mixed models). Models included age and sex, CSF abeta (A), and CSF p-tau (T) as covariates, in addition to the N biomarker.ResultWe included 401 individuals (61±9 years, 42%F, MMSE28 ± 2, vascular comorbidities 8%–19%). N biomarkers were modestly to moderately correlated (range r −0.28 – 0.58). Serum NfL and GFAP correlated most strongly (r 0.58, p < 0.01). T-tau was strongly correlated with p-tau (r 0.89, p < 0.01), although these biomarkers supposedly represent separate biomarker groups. All N biomarkers individually predicted clinical progression, but only HV, NfL and GFAP added predictive value beyond abeta and p-tau (HR 1.52 (95%CI 1.11–2.09); 1.51 (1.05–2.17); 1.50 (1.04–2.15)). T-tau, HV and GFAP individually predicted MMSE slope (range beta −0.17 – −0.11, p < 0.05), but only HV remained associated beyond abeta and p-tau (beta −0.13 (SE 0.04), p < 0.05).DiscussionIn cognitively unimpaired elderly, correlations between different N biomarkers were only moderate, indicating they reflect different aspects of neurodegeneration and should not be used interchangeably. T-tau was strongly associated with p-tau (T), which makes it less desirable to use as measure for N. HV, NfL and GFAP predicted clinical progression beyond A and T. Our results do not allow to choose one most suitable biomarker for N, but illustrate the added prognostic value of N beyond A and T.Classification of EvidenceThis study provides Class II evidence that HV, NfL and GFAP predicted clinical progression beyond A and T in individuals with SCD.

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Section: Classification Of Evidencementioning

confidence: 99%

Section: Classification Of Evidencementioning

confidence: 99%

Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline

et al. 2022

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“…In DS and autosomal-dominant AD, all subjects eventually develop AD pathological changes with time 4,25 . In these populations, AD biomarkers show some degree of co-linearity in the AD continuum, more so than in healthy controls 26 , although with different temporality 4,25 . Therefore, the greater variability of AD pathological changes in the general population facilitates the accuracy to detect amyloid positivity.…”

Section: Discussionmentioning

confidence: 93%

Phosphorylated tau181 in plasma as a potential biomarker for Alzheimer’s disease in adults with Down syndrome

et al. 2021

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Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73–0.87] and 0.92 [95% CI 0.89–0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS.

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“…Adding more generalized markers for neurodegeneration could result in different classification results. 39 The ATN framework was primarily developed to provide a common classification method for patients within the AD continuum. Our study underlines that the ATN framework could be applied in non-AD cases, especially in DLB, where mixed pathology is common.…”

Section: Discussionmentioning

confidence: 99%

“…40,41 When expanding the framework with markers for non-AD pathologies, more generalized markers should be used to define the N, such as neurofilament light or FDG-PET, as they are more sensitive in detecting neurodegeneration caused by any pathology. 39 Among the strengths of our study is the relatively large sample size with longitudinal data available. Some limitations should be noted.…”

Section: Discussionmentioning

confidence: 99%

Association of the ATN Research Framework With Clinical Profile, Cognitive Decline, and Mortality in Patients With Dementia With Lewy Bodies

et al. 2022

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Background and Objectives:The ATN framework has been developed to categorize biological processes within the Alzheimer’s disease (AD) continuum. Since AD pathology often coincides with dementia with Lewy Bodies (DLB), we aimed to investigate the distribution of ATN profiles in DLB and associate ATN-profiles in DLB to prognosis.Methods:We included 202 DLB patients from the Amsterdam Dementia Cohort (68±7yrs, 19%F, MMSE: 24±3, DAT-SPECT abnormal: 105/119). Patients were classified into eight profiles according to the ATN framework, using CSF Aβ42 (A), CSF p-tau (T) and medial temporal atrophy scores (N). We compared presence of clinical symptoms in ATN profiles and used linear mixed models to analyze decline on cognitive tests (follow-up 3±2yrs for n=139). Mortality risk was assessed using Cox proportional hazards analysis. Analyses were performed on both the eight profiles, as well as three clustered categories (normal AD biomarkers, non-AD pathologic change, AD continuum).Results:Fifty (25%) DLB patients had normal AD biomarkers (A-T-N-), 37 (18%) had non-AD pathologic change (A-T+N-: 10%/A-T-N+: 6%/A-T+N+: 3%) and 115 (57%) were classified within the AD continuum (A+T-N-: 20%/A+T+N-: 16%/A+T-N+: 10%/A+T+N+: 9%). A+T+N+ patients were older and least often had RBD symptoms. Parkinsonism was more often present in A+T-, compared to A-T+ (independent of N). Compared to patients with normal AD biomarkers, patients in A+ categories showed steeper decline on memory tests and higher mortality risk. Cognitive decline and mortality did not differ between non-AD pathologic change and normal AD biomarkers.Discussion:In our DLB cohort, we found clinically relevant associations between ATN categories and disease manifestation. Patients within the AD continuum had steeper cognitive decline and shorter survival. Implementing the ATN framework within DLB patients aids in subtyping patients based on underlying biological processes and could provide targets for future treatment strategies, e.g. AD modifying treatment. Expanding the framework by incorporating markers for alpha-synucleinopathy would improve the use of the framework to characterize dementia patients with mixed pathology, which could enhance proper stratification of patients for therapeutic trials.

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P2‐230: Challenges Associated With Biomarker‐based Classifications Systems for Alzheimer's Disease

Cited by 6 publications

References 0 publications

Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline

Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline

Phosphorylated tau181 in plasma as a potential biomarker for Alzheimer’s disease in adults with Down syndrome

Association of the ATN Research Framework With Clinical Profile, Cognitive Decline, and Mortality in Patients With Dementia With Lewy Bodies

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